Mexiletine (FIG. 1a) is an effective sodium channel blocker used as an antiarrhythmic and analgesic oral drug. Structure-activity studies in vivo and in vitro of pharmacologically active mexiletine indicate that its (−)-(R) enantiomer binds preferentially to the cardiac sodium channels. In addition, (−)-(R)-mexiletine is also more active than (+)-(S)-mexiletine on native skeletal muscular fibers. The use of mexiletine as a racemate in the treatment of neuromuscular disorders is limited due to its possible side effects. As shown in FIG. 1b, the optically active mexiletine analogue (R)-2 is 27-fold more potent than (R)-mexiletine in producing a tonic block and 23-fold more potent in condition of high frequency of stimulation (phasic block). Recently, racemate (3) shown in FIG. 1c was established as a novel potent blocker of voltage-gated K+ channels using structure-based virtual screening in conjunction with electrophysiological assays in rat hippocampal neurons.
The preparation of mexiletine enantiomers has been reported previously by several groups. Generally, the methods involved resolution of racemic intermediates, enzymatic hydrolysis of an N-acyl derivative, or using a stereospecific, four-step procedure, in 7.2% overall yield. Flippin, et al. reported a convenient procedure for the preparation of stereoisomers of mexiletine, but the scope of products was limited by the availability of chiral substrates and expensive chromium tricarbonyl complexes of aryl halides: hence, some amines were provided in the racemate form. Although Franchini et al. synthesized the stereoisomers of mexiletine analogues, the use of 2-phenyl-oxirane as chiral source restricted the range of mexiletine analogues. Furthermore, the procedure is also controlled by the regio-specificity of the ring-opening reaction, and the possible racemization of the benzylic carbon by the substitution of the alkoxy group by the amine. Hence, a practical and efficient route for the synthesis of highly enantiopure mexiletine analogues is highly desirable.